Sensitivity of [11C]phenylephrine kinetics to monoamine oxidase activity in normal human heart

Phenylephrine labeled with 11C was developed as a radiotracer for imaging studies of cardiac sympathetic nerves with PET. A structural analog of norepinephrine, (-)-[11C]phenylephrine (PHEN) is transported into cardiac sympathetic nerve varicosities by the neuronal norepinephrine transporter and stored in vesicles. PHEN is also a substrate for monoamine oxidase (MAO). The goal of this study was to assess the importance of neuronal MAO activity on the kinetics of PHEN in the normal human heart. MAO metabolism of PHEN was inhibited at the tracer level by substituting deuterium atoms for the two hydrogen atoms at the alpha-carbon side chain position to yield the MAO-resistant analog D2-PHEN.

Paired PET studies of PHEN and D2-PHEN were performed in six normal volunteers. Hemodynamic and electrocardiographic responses were monitored. Blood levels of intact radiotracer and radiolabeled metabolites were measured in venous samples taken during the 60 min dynamic PET study. Myocardial retention of the tracers was regionally quantified as a retention index. Tracer efflux between 6 and 50 min after tracer injection was fit to a single exponential process to obtain a washout half-time for all left ventricular regions.

Although initial heart uptake of the two tracers was similar, D2-PHEN cleared from the heart 2.6 times more slowly than PHEN (mean half-time 155+/-52 versus 55+/-10 min, respectively; P < 0.01). Correspondingly, heart retention of D2-PHEN at 40-60 min after tracer injection was higher than PHEN (mean retention indices 0.086+/-0.018 versus 0.066+/-0.011 mL blood/ min/mL tissue, respectively; P < 0.003).

Efflux of radioactivity from normal human heart after uptake of PHEN is primarily due to metabolism of the tracer by neuronal MAO. Related mechanistic studies in the isolated rat heart indicate that vesicular storage of PHEN protects the tracer from rapid metabolism by neuronal MAO, suggesting that MAO metabolism of PHEN leaking from storage vesicles leads to the gradual loss of PHEN from the neurons. Thus, although MAO metabolism influences the rate of clearance of PHEN from the neurons, MAO metabolism is not the rate-determining step in the observed efflux rate under normal conditions. Rather, the rate at which PHEN leaks from storage vesicles is likely to be the rate-limiting step in the observed efflux rate.